Clinical Pharmacokinetics 2011;courses.washington.edu/bioen316/Assignments/Sheen... · Clinical Pharmacokinetics of Metformin Garry G. Graham,1 Jeroen Punt,1 Manit Arora,1 Richard

Clinical Pharmacokinetics of MetforminGarry G. Graham,1 Jeroen Punt,1 Manit Arora,1 Richard O. Day,1 Matthew P. Doogue,2 Janna K. Duong,1

Timothy J. Furlong,3 Jerry R. Greenfield,4 Louise C. Greenup,1 Carl M. Kirkpatrick, 5 John E. Ray,1

Peter Timmins6 and Kenneth M. Williams1

1 Departments of Pharmacology & Toxicology and Medicine, St Vincent’s Clinical School, University of New South Wales,

Sydney, New South Wales, Australia

2 Department of Clinical Pharmacology, Flinders Medical Centre, Adelaide, South Australia, Australia

3 Department of Nephrology, St Vincent’s Hospital, Sydney, New South Wales, Australia

4 Department of Endocrinology and Diabetes Centre, St Vincent’s Hospital and Diabetes and Obesity Research Program,

Garvan Institute of Medical Research, Sydney, New South Wales, Australia

5 School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia

6 Biopharmaceutics Research and Development, Bristol-Myers Squibb Company, Moreton, UK

Contents

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

1. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

1.1 Literature Searches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

1.2 Statistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

2. Physicochemical Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

3. Pharmacokinetics after Intravenous Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

4. Pharmacokinetics after Oral Administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

4.1 Immediate-Release Tablets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

4.1.1 Single Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

4.1.2 Multiple Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

4.2 Sustained-Release Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

4.2.1 Multiple Doses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

4.3 Transporters and Absorption of Oral Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

4.4 Concentrations of Metformin in the Small Intestine: Relevance to Action of Metformin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

5. Distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

5.1 Transporters and Uptake by Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87

5.2 Organic Cation Transporters and Uptake of Metformin by Skeletal Muscle and Heart. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

5.3 Uptake into Erythrocytes: Possible Value in Monitoring Dosage of Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

5.4 Transport and Pharmacokinetics during Pregnancy and Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

5.5 Transport into Other Tissues. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

6. Clearance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

6.1 Renal Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

6.1.1 Interactions Involving Cation Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

6.2 Lactic Acidosis and Dosage of Metformin in Renal Impairment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

7. Genetic Variants of Transporters and Response to Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

8.1 Therapeutic Plasma Concentrations of Metformin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

8.2 Recommended Dosage Control of Metformin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Abstract Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from

galegine, a guanidine derivative found inGalega officinalis (French lilac). Chemically, it is a hydrophilic base

which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through

REVIEW ARTICLEClin Pharmacokinet 2011; 50 (2): 81-98

0312-5963/11/0002-0081/$49.95/0

ª 2011 Adis Data Information BV. All rights reserved.

cell membranes should be very limited. The mean – SD fractional oral bioavailability (F) of metformin is

55 – 16%. It is absorbed predominately from the small intestine.

Metformin is excreted unchanged in urine. The elimination half-life (t½) of metformin during multiple

dosages in patients with good renal function is approximately 5 hours. From published data on the

pharmacokinetics of metformin, the population mean of its clearances were calculated. The population

mean renal clearance (CLR) and apparent total clearance after oral administration (CL/F) of metformin

were estimated to be 510– 130mL/min and 1140– 330mL/min, respectively, in healthy subjects and diabetic

patients with good renal function. Over a range of renal function, the population mean values of CLR and

CL/F of metformin are 4.3 – 1.5 and 10.7 – 3.5 times as great, respectively, as the clearance of creatinine

(CLCR). As the CLR and CL/F decrease approximately in proportion to CLCR, the dosage of metformin

should be reduced in patients with renal impairment in proportion to the reduced CLCR.

The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by

organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP]

rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of ef-

fect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extru-

sion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in

antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation

transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical

response are also limited. However, intersubject differences in the levels of expression of OCT1 andOCT3 in

the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of

metformin.

Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in pa-

tients treated with metformin. We suggest that the mean plasma concentrations of metformin over a

dosage interval be maintained below 2.5mg/L in order to minimize the development of this adverse

effect.

Type 2 diabetes mellitus has become an epidemic in the past

several decades. Metformin, an oral antihyperglycaemic agent,

is the most widely used drug in the treatment of type 2 diabetes.

It is a biguanide which has supplanted phenformin, another

biguanide (figure 1). These drugswere developed from galegine,

a derivative of guanidine found in Galega officinalis [French

lilac; goats rue] (figure 1).

Unlike the sulfonylureas, metformin is rarely associated

with hypoglycaemia or weight gain. Most commonly, patients

maintain or even lose weight. The International Diabetes

Federation and the American Diabetes Association and

European Association for the Study of Diabetes both recom-

mend that metformin be commenced as the first-line treatment

in all newly diagnosed patients, regardless of age.[1,2] Questions

about the cardiovascular safety of an alternative group of drugs,

the glitazones, have further added to the status of metformin.

The purpose of this review is to summarize the pharmaco-

kinetics of metformin. Passive diffusion of metformin through

cell membranes is low because of the hydrophilic chemical

nature of metformin but it is a substrate for several organic

cation transporters (OCTs) and an aim of this review is to ex-

amine the significance of these transporters in the distribution,

elimination and biochemical effects of metformin in man.

A feature of the activity of metformin is the intersubject dif-

ferences in its clinical response and up to about one-third of

patients do not respond adequately to metformin. Conse-

quently, we have sought to determine if genetic variants of the

(CH2)2NH

NH

NH

NH2

NH

H3CN

NH

NH

NH2

NH

H3C

CH2NH

NH2

NH

CH

CH3C

H3C

Metformin

Phenformin

Galegine

Fig. 1. Chemical structures of metformin, phenformin and the guanidine

derivative, galegine, an active principle of the French lilac.

82 Graham et al.

ª 2011 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2011; 50 (2)

transporters are responsible for intersubject variations in the

pharmacokinetic parameters and clinical response of metfor-

min. The relationship between the plasma concentrations of

metformin and the most severe adverse effect, lactic acidosis,

has also been reviewed. It should be noted that several aspects

of the clinical pharmacokinetics of metformin, particularly the

involvement of transporters, are unclear and further research

is required.

1. Methods

1.1 Literature Searches

Data on the pharmacokinetics and pharmacodynamics of

metformin were examined by searches on MEDLINE (1950 to

15November 2010) andEMBASE (1988 to 15November 2010).

The keywords used were: ‘metformin’ together with ‘pharma-

cokinetics’, ‘metabolism’, ‘half-life’, ‘pharmacodynamics’, ‘lactate’,

‘lactic’, ‘plasma’, ‘erythrocyte’, ‘transporter’, ‘OCT’, ‘MATE’

or ‘PMAT’. Papers were also obtained from the reference lists

of research and review articles. Inclusion criteria were papers

describing the pharmacokinetics of metformin as well as cor-

relations between the pharmacokinetics or plasma concentra-

tions of metformin and the blood concentrations of lactate and

glucose. Recent results on cation transporters were obtained

from databases of the National Center for Biotechnological

Information (www.ncbi.nim.nih.gov/sites/entrez). Papers were

included irrespective of the language. No study could be eli-

minated because of poor quality. Approved product informa-

tion on metformin was also examined.

1.2 Statistics

All data are presented as mean –SD. The population

mean –SD values of the renal clearance (CLR) were calculated

from the mean – SD values from the several individual studies

in subjects with good renal function using the methods of

Sheiner et al.[3] (equation 1):

CLR¼

PN �w �CLRð ÞP

N �wð Þ ðEq: 1Þ

where N = number of subjects in the individual studies and w is

the weight, an integer ranging from 1 to 3. In general, w was set

at 3 when means of replicated studies had been published.

Otherwise, w was set at 1. The population SD was estimated by

the same general procedure. The mean and SD of the popula-

tion values of the apparent clearance after oral administration

(CL/F) and the ratios of CLR and CL/F to creatinine clearance

(CLCR) were determined similarly.[3,4]

2. Physicochemical Properties

Metformin has acid dissociation constant values (pKa) of

2.8 and 11.5[5,6] and, therefore, exists very largely as the hy-

drophilic cationic species at physiological pH values. The pKa

of 11.5 makes metformin a stronger base than most other basic

drugs with less than 0.01% unionized in blood. Furthermore,

the lipid solubility of the unionized species is slight as shown by

its low logP value [log(10) of the distribution coefficient of the

unionized form between octanol and water] of -1.43.[5] Thesechemical parameters indicate low lipophilicity and, consequently,

rapid passive diffusion of metformin through cell membranes is

unlikely. The logP of metformin is less than that of phenformin

(-0.84) because two methyl substituents on metformin impart

lesser lipophilicity than the larger phenylethyl side chain in

phenformin (figure 1).More lipophilic derivatives ofmetformin

are presently being investigated with the aim of producing

prodrugs with better oral absorption thanmetformin itself. The

dose of metformin is quoted as the hydrochloride salt (molec-

ular weight 165.63) but all concentrations in biological fluids

are expressed as the free base (molecular weight 129.16).

3. Pharmacokinetics after Intravenous Administration

Initially, the plasma concentrations of metformin decrease

rapidly after intravenous dosage but it is difficult to quote a

meaningful elimination half-life (t½) because the time course of

plasma concentrations of metformin follows a multiphasic

pattern (figure 2a). The plasma concentration-time curve has

been fitted by both biexponential[8] and triexponential func-

tions.[7,9] The rapid initial decrease in plasma concentrations

leads to the concentrations falling below the limit of assay by

conventional high-performance liquid chromatography after

about 12 hours. The mean terminal t½ in plasma has been re-

ported to range from 1.7 to 4.5 hours (table I) but these values

do not represent the correct estimates of the terminal t½ in plasma

nor the t½ duringmultiple dosage. The concentrations in urine are

much higher than that derived from plasma and have been fol-

lowed up for up to 72 hours (figure 2a). The terminal t½ de-

termined from the rate of excretion in urine is much longer than

from plasma and ranges from about 9 to 19 hours (table I). A

terminal t½ of about 20 hours is supported from the determina-

tion of the plasma t½ following cessation of multiple dosage reg-

imens of metformin (section 4.1.2). The long terminal phase is

due to a compartment that metformin enters and leaves slowly.

This compartment includes erythrocytes (sections 4.1.2 and 5.3).

Despite the long terminal t½, the bulk of the elimination of

metformin occurs during the early phase. Thus, Tucker et al.[7]

Pharmacokinetics of Metformin 83


found that, of the 79% recovered in urine, approximately 95%of this total urinary output of metformin was excreted in the

first 8 hours after dosage.

The most clinically relevant t½ of metformin is the t½ over a

dosage interval during long-term treatment. This is discussed in

section 4.1.2.

4. Pharmacokinetics after Oral Administration

4.1 Immediate-Release Tablets

4.1.1 Single Doses

Peak plasma concentrations of metformin occur approxi-

mately 3 hours after dosage.[7] The peak plasma concentrations

range from 1.0 to 1.6mg/L after a 0.5 g dose, increasing to

about 3mg/L after a 1.5 g dose.[7] The plasma concentrations

decrease rapidly after a single oral dose and, as is the case after

intravenous dosage, the rate of urinary excretion can be fol-

lowed for a longer time than the plasma concentrations and

again indicates a terminal t½ of about 20 hours (figure 2b).[7]

Metformin is also taken up by erythrocytes (section 5.3) from

which the t½ of loss is also about 20 hours (figure 2b).[7,10]

The gastrointestinal absorption of metformin from the im-

mediate-release tablets is incomplete and the bioavailability (F)

shows some intrasubject as well as intersubject variability

(figure 3). From published data on a total of 11 healthy sub-

jects,[7,9] we estimate that the population mean value of F is

55 – 16%. Absorption ceases at about 6–10 hours after admin-

istration irrespective of the amount of metformin that has been

absorbed up to this time (figure 3). This is about the time taken

for the passage of drugs through the stomach and small intes-

tine.[11] Absorption from the stomach is likely to be negligible

and it therefore appears that the absorption of metformin is

confined very largely to the small intestine with negligible ab-

sorption also from the large intestine. This conclusion is con-

firmed by the administration ofmetformin solutions containing

a gamma emitter which show that the plasma concentrations of

metformin commence to decline when the drug starts to arrive

in the large intestine.[12]

The faecal recovery of metformin is 20–30% of an oral dose.[7]

As there is no metformin in faeces after intravenous dosage, the

material in faeces must be unabsorbed material.[7] Furthermore,

there must be no significant biliary or gastrointestinal secretion.

It is recommended thatmetformin should be takenwith food

tominimize gastrointestinal side effects, such as bloating, flatus

and diarrhoea. A high-fat meal has been reported to decrease

the bioavailability of immediate-release tablets ofmetformin by

about 25%[13] although the effect of food is minimal with com-

bination tablets of metformin with other anti-diabetic drugs.[14-16]

The reduced absorption is unlikely to be clinically significant in

most patients.

4.1.2 Multiple Doses

In healthy subjects, the mean plasma concentrations of

metformin fluctuate between about 0.4 and 1.3mg/L during

0.01

0.1

1.0

10

100

0.01

0.1

1.0

10

100

b

a

0

Time (h)

70605040302010

0.01

Met

form

in c

once

ntra

tion

(mg/

L)

Metform

in excretion rate (mg/h)

0.1

1.0

10

100

0.01

0.1

1.0

10

100

0 80604020

Rate of urinary excretionPlasma concentrationBlood concentration

Fig. 2. (a) Time course of mean plasma concentrations and mean rate of

urinary excretion of metformin following a short infusion (0.25 g over 15 min).

(b) Time course of concentrations of metformin in plasma and in blood, and

rate of urinary excretion of metformin in a healthy subject following an oral

dose of 1.5 g. The prolonged elimination half-life from blood is due to the slow

uptake and loss from erythrocytes. The data are from Tucker et al.[7]

84 Graham et al.


dosage with 1000mg twice daily (figure 4).[17] The mean con-

centrations over a dosage interval (average steady-state con-

centrations [Cav,ss]) are 0.86mg/L (table II). Figure 4 shows the

mean time course of plasma concentrations fitted by a one-

compartmentmodel and first-order rate constants (i.e. constant

t½ values of absorption and elimination). There is only slight

deviation from the concentrations predicted from this model

and the actual plasma concentrations. The mean t½ is about

5 hours in these subjects with good renal function (figure 4,

table II). A similar mean t½ of 5.7 hours was calculated from

the data ofHong et al.[21] (table II). This studywas conducted in

diabetic patients with, on average, slightly impaired renal

function (CLCR 83 – 23mL/min), but the t½ values are very

similar to those in healthy subjects.

As judged from the overall plasma concentrations of met-

formin, there is no significant accumulation of metformin

during multiple doses. Thus, the area under the plasma con-

centration-time curve (AUC) after twice-daily dosage for

4 days is very similar to that seen in the first day of dosage.[17]

However, the trough concentrations are about 95% higher than

predicted from the pharmacokinetic parameters on the first day

of treatment.[7] The trough concentrations were even higher

and the discrepancy between actual and predicted trough

concentrations is even greater after treatment for another

7 days. The lack of agreement between the predicted and actual

trough concentrations in plasma is undoubtedly due to the late

slow elimination phase (section 3, figure 2). This late phase in

plasma is clearly seen after termination of multiple-dose treat-

ment with metformin.[19]

As discussed above, there is some intrasubject variation in

the bioavailability of metformin. However, the variation is not

great during multiple dosing, at least under the conditions of a

controlled pharmacokinetic study in which the plasma con-

centrations of metformin were measured over four dosage in-

tervals of 12 hours (figure 4).[17] The mean coefficient of

variation of the AUC values in the individual subjects was only

13% (range 4–23%).

4.2 Sustained-Release Formulations

Sustained-release dosage forms of metformin have been pre-

pared because of the short initial t½ of metformin. Metformin is

not, however, a good candidate for a traditional sustained-release

dosage form because its absorption is limited largely to the small

intestine (section 4.1). A widely used formulation overcomes this

problem to some extent. This sustained-release tablet swells into a

gel-likemass which is designed to slow passage through the pylorus

and thereby prolong gastric residence.[17] Transit through the small

intestine may also be slowed by the formation of this gel-like mass.

The metformin is contained in polymer particles in the polymer-

containing tablet matrix from which it dissolves slowly and then

diffuses through the outer gel-like mass.

An osmotic sustained-release tablet has also been pre-

pared.[22] After single doses, this product has very similar bio-

availability to that seen during dosing with immediate-release

and other sustained-release tablets.

4.2.1 Multiple Doses

During long-term dosing, the absorption of metformin is

slowed considerably by the sustained-release formulation and

maximum plasma concentrations are reached at about 7–8 hours

as opposed to about 3 hours with immediate-release formula-

tion and coinciding, approximately, with the transit time to the

large intestine (figure 4). The values of CL/F increase slightly

with increasing daily dose (table II), presumably due to de-

creased values of F.

Table I. Pharmacokinetic parameters of metformin after intravenous administration

Parameter Tucker et al.[7] Pentikainen et al.[9] Sirtori et al.[8]

Patients (n) 4 3 5

Dose (g) 0.25 0.5 1.0

Duration of collection of blood samples (h) 12 10–12 8

t½ in plasma (h)a 4.5 – 2.1 1.74 – 0.19 1.52 – 0.29

t½ in urine (h)a 19 – 10 8.9 – 1.2

CL (mL/min)a,b 706 – 33 473 – 18 441 – 89

% of drug excreted unchangeda 78.9 – 4.7 99.9 – 1.4 86

Vd (L)a,b 276 – 136 69 – 8 63 – 17

a Values are expressed as mean – SD.

b t½ and Vd estimated from plasma concentrations during the later times after dosage.

CL = apparent total clearance; t½ = half-life; Vd = volume of distribution.



At a dosage of 2 g as sustained-release tablets once daily, the

plasma concentrations of metformin fluctuate from peaks of

about 1.8mg/L to troughs of about 0.16mg/L (figure 4). The

ratio of peak to trough plasma concentrations of metformin

is greater with the sustained-release than with the immediate-

release tablets. This is the result of the longer time between

doses of the sustained-release tablets (typically 24 hours) than

between doses of the immediate-release tablets (about 12 hours)

[figure 4]. The lowering of blood glucose bymetformin develops

over at least 10 days[19,21] indicating that metformin has a long

residence time in the liver or other effect compartments. Con-

sequently, the greater fluctuation of plasma concentrations

should not be clinically significant, as has been observed.[23]

Gastrointestinal intolerance occurs with both the immediate

and sustained-releasemetformin but, on average, the sustained-

release formulation is better tolerated.[24,25] As a result, patients

often show improved gastrointestinal tolerance of metformin if

changed from immediate-release to sustained-release metformin

and the National Institute for Health and Clinical Excellence

now recommends that sustained-release metformin should be

trialled if gastrointestinal intolerance prevents continuation of

the immediate-release preparation.[26] The sustained-release

formulation also allows a once-daily dosing regimenwhichmay

lead to improved adherence.

4.3 Transporters and Absorption of Oral Metformin

Plasma membrane monoamine transporter (PMAT) may be

the major transporter responsible for the uptake of metformin

from the gastrointestinal tract. It is localized on the luminal side

of enterocytes (figure 5).[27] OCT1 andOCT3 are also present in

the small intestine although only low amounts of both trans-

porters are present.[28,29] OCT3 is also localized in the brush

border of enterocytes[30] and may therefore be, in part, a carrier

of metformin into enterocytes. By contrast, OCT1 is localized

in basolateral membranes and cytoplasm of enterocytes and

may transport metformin into interstitial fluid.[30] OCT1 – and,

possibly to a lesser extent, OCT3 – are transporters of met-

formin in the liver (sections 5.1 and 6.1) where they are present

on the basolateral side of hepatocytes, indicating that they

transport metformin into hepatocytes.

Genetic variants of OCT1 and OCT3 have been detected,

many of which show lesser ability to transport metformin into

model cells.[31,32] After oral dosage to healthy subjects, the

plasma concentrations of metformin were slightly higher in

heterozygotes with one of several variant OCT1 transporters

than in persons with the normal (wild-type) OCT1. This in-

dicates that the presently identified OCT1 variants do not lead

0

20

40

60

80

100

0

Time (h)

b

0

20

40

60

80

100a

Subject 1, 45%

Subject 2, 24%

Subject 3, 57%

Subject 4, 80%

% U

nabs

orbe

d

Subject 1, 35%

Subject 2, 58%

Subject 4, 64%

Subject 3, 74%

12108642

0 12108642

Fig. 3. Percentages of oral doses of metformin remaining to be absorbed as

a function of time after (a) a 0.5 g dose and (b) a 1.0 g dose in four healthy

subjects. The plots show the subject identification number and percentage of

metformin absorbed. The percentage absorption of metformin is fairly con-

sistent after the two doses in subject 1, 3 and 4 but dissimilar in subject 2. The

data are from Tucker et al.[7]

86 Graham et al.


to significantly decreased absorption.[31] A possible explana-

tion is, as outlined in sections 6.1 and 7 and table III, that major

changes may be seen only in homozygotes carrying poorly

functioning transporters, but not in heterozygotes. An alter-

native explanation is that carriers, other than OCT1, may be

transporting metformin out of enterocytes.

4.4 Concentrations of Metformin in the Small Intestine:

Relevance to Action of Metformin

The peak concentrations of metformin in the jejunum are up

to about 500 mg/g of tissue.[38] Although it may be difficult to

wash out all the extracellular drug within the brush border, it

does appear that the concentrations within the small intestine

tissue aremuch higher than in other tissues or in plasma, raising

the possibility that a significant site of action of metformin may

be in the small intestine.[39] Modelling of the absorption of

metformin through monolayers of a model cell line, Caco-2

cells, indicates that a substantial proportion of metformin may

be absorbed through the paracellular route (between cells) al-

though the model still allows high concentrations of metformin

to develop within the cells.[40] Although Caco-2 cell monolayers

are very useful in studying drug transport in vitro, the expres-

sion of OCTs, particularly the expression of OCT2 in Caco-2

cells,[30] makes Caco-2 cells different to normal enterocytes.

5. Distribution

Metformin is not bound to plasma proteins.[7] The volume of

distribution (Vd) has been reported to range from 63 to 276L

after intravenous administration (table I). These values re-

present Vd over the last 8–12 hours after intravenous dosage

(table I). Of greater significance is the apparent volume of

distribution after oral administration (Vd/F) estimated during

multiple dosing. During dosage with 2000mg metformin daily,

either as immediate-release or sustained-release tablets, Vd/F is

approximately 600L (table II). As approximately 50% is ab-

sorbed (section 4), the actual Vd duringmultiple dosage is about

300L. This large Vd indicates that there is considerable tissue

uptake of metformin.

The large Vd of metformin is confirmed by studies in mice

and rats. After a single oral dose, concentrations up to seven

times the serum concentrations are found in the kidneys,

adrenal glands, pancreas and liver, with lesser amounts in lung,

muscle and spleen.[41,42] The high concentrations in kidney are

not necessarily due to uptake in kidney tissue and may be due,

in part, to high concentrations ofmetformin in the urinary tract

(section 6).

5.1 Transporters and Uptake by Liver

OCT1 and OCT3 are transporters of metformin in the liver.

The greatly diminished hepatic uptake of metformin in OCT1-

knockout mice indicates that OCT1 is the major transporter in

mice.[33,43] It is widely presumed that this is also the case in man

but the relative activities of OCT1 and OCT3 are still unknown

in man.

Both OCT1 and OCT3 are present in highest levels on the

sinusoidalmembrane (basolateral side) of hepatocytes[32,44] and

thus are located in a position for uptake of metformin from

blood into hepatocytes (figure 4). They could also transport

metformin in the reverse direction, i.e. from liver to blood. Both

transporters are also present, at lower levels, in the cell mem-

brane of cholangiocytes (epithelial lining cells of bile ducts)[44]

where their function is unknown. Metformin is a substrate for

OCT1[33,44-46] and OCT3[32,44] and the recently discovered and

0.1

1.0

72 96 120 144 168

72 96 120 144 168

Met

form

in p

lasm

a co

ncen

trat

ion

(mg/

L)

0.1

1.0

b

a

Time (h)

Fig. 4. Semilogarithmic plots of the time courses of mean plasma con-

centrations during multiple dosing with (a) immediate-release metformin

1000 mg (two 500 mg tablets) every 12 h, and (b) sustained-release met-

formin 2000 mg (four 500 mg tablets) once daily. The best-fit curves were

determined by the use of the Kinetica software program (Thermo Fisher

Scientific, Inc., Waltham, MA, USA). The absorption kinetics are described by

a constant half-life of absorption (first-order) and constant rate of absorption

(zero-order) over 7.6 h, for the immediate-release and sustained-release

tablets, respectively. A constant half-life was applied in both cases. The data

are from Timmins et al.[17] in 14 to 16 healthy subjects.



very considerable variation in the hepatic expression of OCT1

may be of great significance in the clinical response to metformin

because its major effect may be in the liver.[33] The large inter-

subject variation in the hepatic levels of OCT1 was detected by

both the variation in the transporter protein (83-fold) and also

in the corresponding messenger RNA (mRNA) [113-fold]. The

importance of OCT1 expression may be important, as shown

for imatinib. Low activity of OCT1 in mononuclear cells cor-

relates with resistance to imatinib and requires higher than

normal doses of the drug.[47]

As yet, the intersubject differences in the expression ofOCT3

have only been detected by the 27-fold intersubject variation in

the mRNA, and intersubject differences in the expression of

OCT3 protein, although likely, have not been examined.[44]

These discoveries on variable expression ofOCT1 andOCT3

have been made in normal sections of human livers taken at

surgery. The patients were taking a variety of drugs and an

influence of these drugs on the variation of OCT1 and OCT3

is possible. The levels of both OCT1 and OCT3 were lower in

livers in patients with cholestasis than in livers in other patients

although there was considerable overlap between the two

groups.[44] The expression of OCT1 and OCT3 was also lower in

patients carrying some variant transporters. As the clinical res-

ponse to metformin shows considerable intersubject variation, it

will be of great interest to determine if the variable response can be

related to the hepatic expression of OCT1 or OCT3.

Multidrug and toxin extrusion transporter (MATE)-1 has

been proposed to mediate the transport of metformin into bile

canaliculus as it is present at this site and is a carrier of met-

formin.[48,49] However, metformin is not present in faeces after

intravenous administration although it is present after oral

dosage (section 4.1.1). The biliary excretion of metformin

therefore appears insignificant in man although resorption in

the biliary tract following initial secretion is possible. MATE1

is also present in the kidney where it probably transports met-

formin from kidney tubule cells into urine (section 6.1).

5.2 Organic Cation Transporters and Uptake of

Metformin by Skeletal Muscle and Heart

Both OCT1 and OCT3 are expressed in skeletal muscle

which may be a major site of action of metformin. The ex-

pression of mRNA of OCT3 is higher than that of OCT1 but

the relative levels or activities of the two OCT proteins is un-

known.[32] Several coding and intronic variants of OCT3 have

been detected but the influence of these variants on the clinical

response to metformin has not been determined. The actual

uptake by skeletal muscle in man is not known but the concen-

tration ratio is only about 1.5 in mice and, not surprisingly, is little

reduced by OCT1 knockout.[45] As in skeletal muscle, the mRNA

of OCT3 in heart is greater than mRNA of OCT1 but again, the

relative activities of the two transporters are not known.[32]

Table II. Pharmacokinetic parameters of metformin during multiple-dosing regimens in healthy subjects (HS) or patients with type 2 diabetes mellitus (DM) with

good renal functiona

Dosage (mg) n Cmax (mg/L) Cav,ss (mg/L) CL/F (mL/min) Vd/F (L) t½ (h) Reference

Immediate-release

HS, 250 mg bid 24 0.65 – 0.11 0.35 – 0.06 780 – 139 NA NA 18

DM, 850 mg tid 9 1.90 – 0.63 1.35 – 0.50 1118 – 325 1952 – 1519b 19.8 – 15.9b 19

HS, 850 mg tid 9 2.01 – 0.39 1.34 – 0.35 1130 – 457 1211 – 690b 13.0 – 7.8b 19

DM, 1000 mg bid 13 2.09 – 0.56 1.23 – 0.30 881 – 215 NA NA 20

HS, 1000 mg bid 15 1.32 – 0.23 0.86 – 0.19 1265 – 274 559 – 163 5.1 – 1.0 17

DM, 850 mg bidb 12 NA 0.70 – 0.06 1316 – 113 648 – 13.8 5.7 – 1.3 21

Sustained-release

HS, 500 mg od 16 0.60 – 0.17 0.26 – 0.08 1029 – 325 463 – 204 5.2 – 1.6 17

HS, 1000 mg od 16 1.08 – 0.26 0.52 – 0.13 1033 – 260 402 – 123 4.5 – 0.8 17

HS, 1500 mg od 15 1.44 – 0.36 0.70 – 0.17 1159 – 287 481 – 129 4.8 – 0.5 17

HS, 2000 mg od 14 1.80 – 0.29 0.85 – 0.17 1271 – 256 572 – 175 5.2 – 1.2 17

a Values are expressed as mean – SD.

b Vd/F and t½ are the pharmacokinetic parameters determined during the terminal log-linear phase elimination following termination of treatment and therefore

do not represent the parameters over a dosage interval.

bid = twice daily; Cav,ss = average plasma concentration at steady state over a dosage interval; CL/F = total clearance after oral administration; Cmax = maximum

plasma concentration; NA = not available; od = once daily; t½ = elimination half-life; tid= three times daily; Vd/F = volume of distribution after oral administration.

88 Graham et al.


5.3 Uptake into Erythrocytes: Possible Value in

Monitoring Dosage of Metformin

An unusual aspect of the pharmacokinetics of metformin is

its slow uptake into erythrocytes (figure 2b). After single doses,

the peak concentrations are much higher in plasma than in

erythrocytes. The subsequent decline of concentrations in ery-

throcytes is much slower than in plasma and, after about 6 hours,

the concentrations in erythrocytes exceed those in plasma. The

mean terminal t½ is about 20 hours in erythrocytes and is

therefore very similar to the terminal t½ ofmetformin in plasma

and urine (section 4, figure 2b).[7,10] During long-term dosing,

the concentrations in erythrocytes should fluctuate to a much

lesser degree than in plasma.[10]

Monitoring the plasma concentrations of metformin is not

standard clinical practice but it has been suggested that mon-

itoring the concentrations in erythrocytes could assist the dos-

age optimization.[10] The relatively stable concentrations in

erythrocytes should allow an evaluation of the exposure of

patients to metformin over the previous 1 to 3 days. Erratic

dosage times and intrasubject variation in the rate or extent of

absorption should have lesser effects on the concentrations in

erythrocytes than in plasma.

Two procedures have been used to measure the concentra-

tions in erythrocytes. Robert et al.[10] assayed metformin in

erythrocytes after centrifugation and washing the cells three

times with normal saline. The alternative method is to measure

the haematocrit (H) of the blood sample and to assay the

concentrations in whole blood (Cb) and plasma (Cp). The

concentrations in erythrocytes (Ce) is then calculated from

equation 2:

Ce¼Cb� ð1�HÞ �Cp

H ðEq: 2Þ

5.4 Transport and Pharmacokinetics during

Pregnancy and Lactation

Metformin is increasingly being used to treat gestational

diabetes.[50-52] Metformin is carried across the placenta by

transporters[53] and the concentrations in the fetus are only

slightly lower than in the mother. Further, the plasma metformin

concentrations are lower in pregnancy than in non-pregnant

women if the dosage is not altered,[54,55] due to its greater CLR

which is the result of the higher glomerular filtration rate

(GFR) during pregnancy.[56] CLR and CL/F may be increased

Table III. Variants of organic cation transporters (OCTs) and renal clearance (CLR) of metformin

Variant transporter,

nucleotide,

amino acid change

Uptake in vitro into

cells expressing variant

transporter (% of control)

CLR of metformin in variants

(% of control CLR [95% CI] {n = no. of subjects in normal, variant groups})

OCT1 SLC22A1

181C>T, Arg61Cys 7[33] Heterozygotes (1 normal allele + 1 or more of 4 variant alleles)

1201G>A, Gly401Ser 100[33] 1 or 2 variant alleles, 95 [52, 138] {n = 8, 12}[31,34]a

1256delARG, Met420Del 30[33] 1 variant allele, 108 [99.5, 117] {n = 51, 48}[34,35]

1393G>A, Gly465Arg 3[33] 2 variant alleles, 121 [109, 134] {n = 51, 4}[34,35]

OCT2 SLC22A2

808G>T, Ala270Ser 150,[36] 60[37]b Heterozygotes (1 normal allele + 1 variant allele)

95 [87, 103] {n = 113, 39}[34]

Homozygotes {2 variant alleles}

60 [46, 74] {n = 15, 10}[34]

a One subject was homozygous with respect to the variant transporter, Arg61Cys.

b Contrasting results may be due to differing cellular expression of variant transporter.

EnterocyteSmallintestine

OCT1Blood

HepatocyteBlood

Renal tubule cell Urine

PMATOCT3

OCT1OCT3

OCT2Blood

OCT1MATE1MATE2K

Fig. 5. Major known transporters involved in the absorption, hepatic uptake

and urinary excretion of metformin. MATE = multidrug and toxin extrusion

transporter; OCT = organic cation transporter; PMAT = plasma membrane

monoamine transporter.



by about 50% during mid-pregnancy.[56] Increasing dosage

during pregnancy and reducing dosage back to usual levels

after delivery should be considered.[54]

There is minimal transport of metformin into milk with

the estimated dose being less than 0.3% of the mother’s dose

even when calculated on the basis of their relative body-

weights.[57]

5.5 Transport into Other Tissues

Both OCT1 and OCT3 are found in many tissues. OCT1 is

located predominately in the liver with much lower con-

centrations in several other tissues.[44] The level of OCT1

mRNA is substantial in the adrenal gland although the ex-

pression is still much lower than in the liver. OCT3 is present in

many tissues, apart from the liver, with the highest levels of the

mRNA in the adrenal gland. The high levels of OCT1 and

OCT3 in the adrenal gland are consistent with the substantial

levels of metformin at this site.[41] In mice, MATE1 is found in

many tissues, including A (glucagon-secreting) cells of the islets

of Langerhans but not in B (insulin-secreting) cells.[58] As is the

case in humans, high levels of MATE1 are also present in the

adrenal cortex.[58] Correlations between the mechanism of ac-

tion ofmetformin and its distribution in specific tissues requires

examination.

6. Clearance

Excretion of unchanged drug in urine is the major mode of

elimination of metformin. No metabolites of metformin have

been found in urine[7,9,41] although different drug recoveries are

reported in urine. Pentikainen et al.[9] administered 14C-labelled

metformin intravenously and found 100% recovery of un-

changed drug in urine (table I). By contrast, Tucker et al.[7] and

Sirtori et al.[8] could not account for approximately 20% of the

drug, using chromatographically based assays of unlabelled

drug. No drug is, however, found in the faeces after intravenous

dosage.[7,9] Thus, it is still possible that small proportions of

doses of metformin may be metabolized or excreted by non-

renal routes. Despite this uncertainty, it is clear that the CLR

of metformin is very high and is the major mode of elimination

of metformin.[7] The estimated population mean (– SD) of

CLR is 507 – 129mL/min in subjects with good renal function

(table IV).[7-9,14,19,35,36,59-61] Three factors probably contribute

to its high CLR:

(i) Metformin is a small molecule which is not bound to plasma

proteins and, therefore, is readily filtered at the glomerulus.

(ii) Metformin is a substrate for several transporters in the

kidney (section 6.1).

(iii) The low lipid solubility of metformin should lead to

negligible passive resorption (section 2).

Table IV. Renal clearance (CLR) of metformin in healthy subjects (HS) and patients with diabetes mellitus (DM). All doses were oral except where noted after

the dose. All subjects and patients had good renal function

Dose Subjects n No. of studies

on each subject

CLR (mL/min) Reference

500 mg single dose HS 5 1–2 446 – 56 9

250 mg IV, 1000 and 1500 mg HS 4 3 494 – 110 7

1000 mg single dose HS + DM 8 1 280 – 127 7

1000 mg single dose HS 5 1 597 – 196 59

850, 1700 and 2550 mg single doses, 850 mg tid DM 9 4 519 – 205 19

850, 1700 and 2550 mg single doses, 850 mg tid HS 9 4 521 – 144 19

850 mg single dose HS 6 1 636 – 84 60

927 mg IV single dose HS 5 1 335 – 103 8

550 mg single dose HS 12 1 395 – 135 14

259 mg od HS 7 1 527 – 165 61

500 mg single dose HS 103 1 533 – 117 35

850 mg single dose HS 14 1 441 – 108 36

Population mean – SD 505 – 129

IV = intravenous; od = once daily; tid = three times daily.

90 Graham et al.


As expected, the CLR ofmetformin decreases approximately

in proportion to decreasing renal function down to the lowest

level of renal function measured, i.e. to a CLCR of about

20mL/min (figure 6a).[7-9,59,60] The ratio of the CLR to the

CLCR is quite variable, 4.3 – 1.5. In part, this variation may be

due to the difficulty in collecting complete timed samples of

urine formeasurements of CLR although careful measurements

of the CLR of metformin indicate that it varies little in in-

dividual subjects.[62] Intersubject differences in the tubular

transport of metformin are likely and may also be due to either

the presence of genetic variants or variable expression of the

transporters (section 6.1).

Age is an independent variable which correlates negatively

with the CLR of metformin (i.e. for any particular value of CLR,

the CL/F of metformin decreased as age increased).[35,60] How-

ever, the influence of age ismuch smaller than the effect of CLCR.

From measurements after single and multiple doses, the

population CL/F is estimated to be 1140 – 330mL/min from

data in subjects with good renal function (CLCR >80mL/min).[5,7,9,17-22,35,36,60,63] CL/F increases slightly with in-

creasing multiple doses (table II), probably due to slightly de-

creasing fractional absorption (F). CL/F is higher than that of

CLR, as F is about 0.5 (section 4.1.1). Not surprisingly, a sig-

nificant correlation is seen between the CL/F of metformin and

the CLCR (figure 6b). The population estimate of the ratio of

the CL/F to the CLCR is 10.7 – 3.5.

The proportional relationship between both CLR and CL/Fwith CLCR indicates that the maximal dosage of metformin

should be decreased in line with decreasing renal function.

Many diabetic patients have impaired renal function and this is

an important aspect of the control of metformin dosage. On the

other hand, some patients have CLCR well above the average of

120mL/min and, not unexpectedly, the CLR of metformin may

be very high. For example, the data of Tzvetkov et al.[35] in-

dicate that the mean CLR is approximately 600mL/min when

the CLCR is 150mL/min. Higher dosages than usual may be

considered in such patients if the clinical response to standard

dosage is inadequate.

6.1 Renal Transporters

Several cation transporters are present in the kidney:

(i) OCT1, OCT2 and OCT3: OCT2 has been studied in most

detail. It is located on the basolateral (blood) side of renal

tubular cells and transports metformin into the proximal

tubular lining cells (figure 5). OCT1 has been linked to the

hepatic uptake of metformin (section 5.1) but has recently been

detected in the apical membranes (luminal side) in the proximal

and distal tubules [35] The site of OCT1 indicates that it is

involved in the secretion of metformin although resorption is

possible. OCT3 mRNA is also expressed in the kidney.[32]

0

500

1000

1500

2000

2500

0

CLCR (mL/min)

b

a

Met

form

in C

L/F

(m

L/m

in)

18016014012010080604020

0

200

400

600

800

Met

form

in C

LR (

mL/

min

)

0 18016014012010080604020

Fig. 6. (a) Relationship between renal clearance (CLR) of metformin and the

clearance of creatinine (CLCR). The data are from Tucker et al.[7] (grey cir-

cles), Pentikainen et al.[9] (black circles), Sirtori et al.[8] (grey squares) and

Noel[59] (black squares) in individual subjects, and the mean – SD data are

from Sambol et al.[60] (black inverted triangles). The horizontal bars indicate

the SDs of the CLR. The correlation was significant (r = 0.88, p < 0.001). The

line of best fit was calculated from the population mean ratio of the clearances

(4.3). (b) Relationship between apparent clearance after oral administration

(CL/F) of metformin and the CLCR. The data are from individual subjects of

Tucker et al.[7] (grey circles), Sirtori et al.[8] (grey squares) and Hong et al.[21]

(grey triangles), and the mean – SD data are from Sambol et al.[60] (black

inverted triangles). The horizontal bars indicate the SDs of the CLR. The

correlation is significant (r = 0.66, p = <0.01). The line of best fit was calculated

from the population mean ratio of the clearances (10.7).



(ii)MATE1 andMATE2K:MATE1 occurs in the brush border

and probably transportsmetformin out of the tubule lining cells

into urine. The transporter MATE2K, a splice variant of

MATE2, is also present in the brush border and may be the

major transporter of metformin into urine.[48,64]

(iii) PMAT has been recently detected in the podocytes in the

glomerulus.[28,65] Its function in podocytes is not known.

The influence of four common low-activity variants of OCT1

on CLR of metformin has been studied. Heterozygotes carrying

only one of the four common variants showno significant changes

in the CLR but heterozygotes carrying two low-activity alleles

have higher CLR than normal subjects (table III). However, the

number of subjects with two low-activity variants was only four

and the percentage increase in CLR was only 21% (table III),

therefore further examination of this finding is required.

The intron variant, rs1867351, promotes the expression of

OCT1 in lymphoblastoid cell lines but does not alter the CLR of

metformin in heterozygotes.[35]

Of the variants of OCT2, the Ala270Ser (rs316019, 808G>T)may be the most important because of the high frequency

(10–15%) of this allele in several populations.[28] However, the

results are inconsistent. Chen et al.[36] reported that CLR and

CL/F were higher in Caucasian and African-Americans het-

erozygotes carrying this variant than in normal homozygotes

although there was considerable overlap of both clearances.

However, Tzvetkov et al.[35] found no significant effect of the

Ala270Ser transporter on CLR in Caucasian heterozygotes

while Song et al.[37] reported a lower clearance in a smaller

number of heterozygous Korean subjects. Combining all the

results on CLR and ignoring possible racial differences in the

expression of transporter variants, there is no significant dif-

ference between normals and heterozygotes carrying the var-

iant Ala270Ser transporter.[34] Zolk[34] suggested that the lack

of effect of the variant transporter in heterozygotes is due to the

variant gene being recessive. To be consistent with the dom-

inant/recessive hypothesis, a decreased CLR should be seen in

homozygotes carrying the variantOCT2 transporter, as is the case

(table III). The CLR is lower in twoAsian groups of homozygotes

carrying the variant Ala270Ser transporter than in normal homo-

zygotes[37,66] but there are no data on the pharmacokinetics in

homozygotes in Caucasian and African-American groups carry-

ing the variant because of the rarity of such homozygotes.

The expression of OCT2 mRNA in human kidney varies

over 100-fold.[67] As is the case withmRNAofOCT1 in the liver

(section 5.1), it is likely that the variable mRNA leads to con-

siderable intersubject variation in the expression of OCT2

protein and, potentially, in the CLR of metformin. There is,

however, no information on the levels of OCT2 protein in the

human kidney. It is of note that the data on the expression of

OCT2mRNAmay possibly be affected by the patients’ cancers

or treatment as the samples were obtained from apparently

normal parts of kidney cortex taken from nephrectomized

patients.[67]

Several coding variants of OCT3 have been detected[32] but

several variants, even in homozygotes, have not significantly

altered the CLR of metformin.[68] Heterozygotes carrying one

of several coding variants of MATE1 and MATE2K also did

not alter the CL/F of metformin but, as yet, there is no in-

formation on the CL/F in homozygotes.[69]

6.1.1 Interactions Involving Cation Transporters

Cimetidine is a substrate for cation transporters and de-

creases the CLR of a low daily dose of metformin (250mg).[61]

The inhibitory effect of cimetidine may be dependent upon the

transporter variant. Thus, cimetidine (400mg daily) decreases

the CLR of metformin to a mean of 48% in subjects containing

the reference OCT2, to 32% in subjects who are heterozygous

with respect to a variant (OCT2-270S) and to 19% of control

values in homozygotes of the same variant.[66] Interaction by

cimetidine through MATE1 is also possible.[70,71] Pyrimetha-

mine inhibits MATE1 and MATE2K in vitro[72] but this po-

tential interaction has not been examined in man.

Many drugs, like cimetidine,metformin and pyrimethamine,

are basic – i.e. they are cationic to a greater or lesser extent at

physiological pH. Consequently, other basic drugs, such as

antihistamines, antidepressants and opioid analgesics, could

possibly decrease CLR of metformin. Conversely, metformin

may decrease the CLR of other basic drugs that are excreted

largely unchanged (e.g. amphetamines).

Combination tablets ofmetforminwith a variety other drugs

have been formulated and there are studies on possible phar-

macokinetic interactions with glyburide,[14] vildagliptin,[73]

sitagliptin,[20] rosiglitazone[74] andGinkgo extract.[75] The effects

of these other drugs on CL/F of metformin or of metformin on

CL/F of other drugs are, at most, small and not clinically sig-

nificant. Aliskiren[76] (a direct renin inhibitor), memantine[18]

(a drug used for Alzheimer’s disease) and the antibacterial ce-

phalexin[77] also have insignificant effects on the CL/F of met-

formin. Although several of these compounds (vildagliptin,

sitagliptin, rosiglitazone and memantine) have basic nitrogen

groups and exist, to some degree, as cations at physiological pH

values and could be potential substrates for cation transporters,

they do not exhibit significant interactions with metformin.

A variety of basic drugs inhibit the in vitro uptake of metformin by

HEK293 cells expressing OCT2 but of the several drugs tested,

only fenfluramine and mexiletine, in addition to cimetidine,

92 Graham et al.


were detected as interacting significantly with the uptake of

metformin in vitro.[78] These drugs should be evaluated in vivo.

This study of Zolk et al.[78] also indicated a general molecular

structure of drugs which may inhibit OCT2 and, consequently,

the CLR of metformin.

6.2 Lactic Acidosis and Dosage of Metformin in Renal

Impairment

The occurrence of lactic acidosis during treatment with

metformin is of great clinical concern as the death rate is up to

50%. It is diagnosed when a patient has a blood pH <7.35 and

plasma lactate concentrations >5.0mmol/L.[79] Lactic acidosiswas associated with the older biguanides, phenformin and bu-

formin, and the product information (label) on metformin

contains statements such as: ‘‘Life-threatening lactic acidosis

can occur due to accumulation of metformin. The main risk

factor is renal impairment. Other risk factors include old age

associated with reduced renal function and high doses of met-

formin above 2 g/day.’’ It is therefore commonly stated that

metformin should only be prescribed if patients’ CLCR or GFR

is above a defined low limit. The problem for prescribers is that

the statements on the limit are inconsistent and, furthermore,

there is considerable doubt about these recommendations. The

product information contains the statement that metformin

should not be prescribed in patients with GFR values below

60mL/min. Other references include both lower (30mL/min[80])

and higher (90mL/min[81]) limits. The higher limit was sug-

gested to ‘ensure an adequate margin of safety’ but if this were

the lower limit of GFR for the prescription of metformin, a

large proportion of diabetic patients would not receive the drug.

Recent surveys indicate that metformin is commonly prescribed

for patients with estimated GFRs down to 30mL/min[82] and, in

small numbers of patients, at even lower CLCR.[83]

Despite the warnings in the product information about the

danger of lactic acidosis during treatment with metformin,

there is still considerable discussion and question about met-

formin being a significant cause of lactic acidosis. A recent

estimation of the incidence of lactic acidosis is 3.3 cases per

100 000 patient years of treatment with metformin.[84] It is of

note that lactic acidosis also develops during treatment with the

other major group of oral antihyperglycaemic drugs, the sul-

fonylureas, where the incidence of lactic acidosis was estimated

as 4.8 per 100 000 patient years.[84] Furthermore, no case of

lactic acidosis was recorded in clinical trials on metformin.[79]

These trials included studies over more than 70 000 patient-

years of metformin treatment but patient selection to exclude

patients with risk factors for lactic acidosis and good patient

care may well have contributed to the absence of this adverse

effect in these clinical trials.

Although lactic acidosis is clearly uncommon during treat-

ment with metformin, there is little doubt that high con-

centrations of metformin can cause lactic acidosis. First, acute

overdoses taken with suicidal intent have caused lactic acido-

sis.[85-88] Furthermore, plasma lactate begins to increase when

plasmametformin concentrations are greater than about 20mg/L(150 mmol/L) in rats[45] and, in an excellent survey of reports of

lactic acidosis in patients, Lalau and Race[89] recorded plasma

concentrations of metformin of 20–107mg/L (150–820 mmol/L)in 24 of 49 patients with lactic acidosis. An even greater pro-

portion may have had plasma concentrations above 20mg/L as

the time between the development of the acidosis and the col-

lection of plasma samples for the assay of metformin was not

recorded well. Although the dosage of metformin is reduced in

renal impairment in order to prevent lactic acidosis, it is notable

that lactic acidosis may occur in patients whose renal function

was previously normal.[90]

It now appears that most patients can take metformin safely

for prolonged periods but, in a very small proportion of treated

patients, lactic acidosis and renal impairment develop over a

short time.[91] In many cases, the lactic acidosis has followed

prolonged vomiting and/or diarrhoea.[90] We suggest that in

these patients, dehydration might have caused acute renal fail-

ure, reduced CLR of metformin and increased plasma con-

centrations of metformin when its dosage was continued. This

may very well exacerbate, or even cause, the acidosis. Diabetic

patientsmaybemore prone to the development of lactic acidosis

for a number of reasons, including their microvascular disease.

7. Genetic Variants of Transporters and Response

to Metformin

Variation in the response of patients due to genetic variants

of cation transporters has been sought because of the im-

portance of transporters in the absorption, distribution and

elimination of metformin and the considerable interpatient

variation in the response of metformin. Several genetic variants

of OCT1 show impaired transport of metformin into model

cells in vitro.[28,46] Low-transporter-activity genetic variants in-

clude Arg61Cys (181C>T, single nucleotide [SNP] rs12208357),

Gly401Ser (1201G>A,SNPrs34130495),Met420del (1256delATG,

SNP rs72552763) and Gly465Arg (1393G>A, SNP rs34059508)

[table III]. Met420del is the most common, with an allele

frequency of 18.5% in Caucasian subjects although much lower

in African Americans (2.9%) and an even lesser frequency in

Japanese and Koreans.[28] All these non-synonymous genetic



variants are on exons and therefore lead to variations in the

amino acid composition of OCT1.

At present, there is no clear cut major effect of the presence

of these variants of OCT1 on the pharmacokinetics in vivo

(section 5.1) or on the clinical response in patients expressing

these variants. In the glucose tolerance test in individuals ad-

ministeredmetformin, the increase in blood glucosewas slightly

greater in healthy subjects carrying one or two of these reduced

function OCT1 variants than in subjects with the normal

OCT1.[33] By contrast, fasting blood glucose of women with

polycystic ovary syndrome was not influenced by the genes for

up to three variants of OCT1, although total cholesterol and

triglycerides in plasma decreased in patients with the reference

genotype but not in carriers of the variants.[92] Furthermore, a

recent study has found that the presence of two of these var-

iants, Arg61Cys and Met420del (table III), did not impair the

effect of metformin on blood glucose in diabetic patients.[93] In

all three studies, almost all subjects carrying the variant genes

were heterozygotes. Zolk[34] has suggested a recessive model

(i.e. the presence of variantsmay only have a significant effect in

homozygotes carrying the variant transporter) [table III]. In the

liver, the utility of both OCT1 and OCT3 as transporters of

metformin may decrease any effect of dysfunctional variants

on the activity of either transporter alone and on the hepatic

uptake of the drug. Furthermore, the variation in the expres-

sion of OCT1 and OCT3 in the liver may be a considerable

cause of interpatient differences in the response to metformin

(section 5.1).

Reduced antihyperglycaemic response to metformin has

been found in patients carrying an intronic variant of OCT1

(A>C, SNP rs622342)[94] while there is a larger response in

patients who have an intronic variant of the MATE1 (G>A,

SNP rs2289669) transporter. In both cases, homozygotes car-

rying the variant genes have greater changes in the anti-

hyperglycaemic response than is seen in heterozygotes.[95] Not

surprisingly, there is an interaction between the response to

metformin in patients carrying the two variants, such that the

least beneficial effect on blood glucose was found in homo-

zygotes for both the variant OCT1 and normalMATE1.[96] The

blood glucose in this group actually increased during treatment

with metformin. The CLR of metformin is unaltered in patients

carrying the MATE1 variant (G>A, SNP rs2289669), both in

heterozygotes and homozygotes.[35] As both genetic variants

OCT1 andMATE1 are in introns, the mechanism of the altered

effect of metformin is not known. Possibilities include changes

in the expression of the normal or variant transporters. Another

intronic variant of MATE1 (C>T, SNP rs8065082) is possibly

associated with a lesser progression of prediabetes to dia-

betes[97] but there has been no study on any influence on the

pharmacokinetic parameters.

8. Conclusions

8.1 Therapeutic Plasma Concentrations of Metformin

The clinical effects of metformin develop slowly over several

days of treatment at least[21] and the range of plasma con-

centrations over a dosage interval depends upon the formula-

tion (figure 4, section 4.2) without any significant effect on the

clinical response.[23] Consequently, we suggest that the Cav,ss

should provide the best correlate with the clinical effects of

metformin, better than the trough or peak concentrations.

The plasma concentrations of metformin have been re-

corded in a number of studies (table V) with most emphasis on

the concentrations which are not associated with lactic acidosis.

We are presently developing pharmacokinetic programs for

estimating the values of Cav,ss, from the plasma concentrations

of metformin collected at various times after dosage. Our initial

Table V. Recorded or recommended plasma concentrations of metformin

Metformin dosage (g) Plasma concentration (mg/L) Comments Reference

Various Ctrough up to 2.24 No correlation with plasma lactate 8

Various Cav,ss up to 1.5 Slight increase in plasma lactate with increasing plasma

concentrations of metformin

98

Various Cav,ss up to 2.5 No correlation between plasma lactate and metformin 99

1 g immediate-release bid Ctrough 0.5 – 0.4

Cmax 1.6 – 0.5

100

Not stated 0.6 – 0.5 Recommended as normal concentration; presumably Ctrough 91

Not stated <5 Recommended; presumably Cmax 101

3 g daily Cav,ss 1.4 – 0.4 Calculated from CL/F of 1140 – 330 mL/min Present review

bid = twice daily; Cav,ss = average concentration at steady state over a dosage interval; CL/F = apparent clearance after oral administration; Cmax = maximum

plasma concentration; Ctrough = trough plasma concentration.

94 Graham et al.


finding is that 75 of 76 patients had achieved Cav,ss values up to

2.5mg/L.[99] No patient developed lactic acidosis and, tenta-

tively, we propose this to be an upper level (table V).

Considering that themaximal recommendeddose ofmetformin

is 3 g in most countries, we have estimated the values of Cav,ss

from the mean population estimates of CL/F. For example,

the mean population estimate of CL/F is 1140 – 330mL/min

(section 6). Accordingly, the values of Cav,ss at 3 g metformin

HCl (= 2.34 g metformin base) daily are estimated to be

1.4 – 0.4mg/L (table V). These calculated values of Cav,ss could,

however, be slightly overestimated because the CL/F of met-

formin increases slightly as the dosage increases (table II,

section 4). Overall, these estimated values of Cav,ss are con-

sistent with our tentative recommendation of a maximal value

of Cav,ss of 2.5mg/L.It should be emphasized that these recommendations about

Cav,ss have been made largely from considerations of toxicity

due to lactic acidosis. Optimal concentrations for lowering

blood glucose are unknown at this stage. Furthermore, careful

monitoring of the plasma concentrations and correlations with

the concentrations of both glucose (or glycosylated haemo-

globin [HbA1c]) and lactate are required in order to demon-

strate the value of therapeutic drug monitoring.

8.2 Recommended Dosage Control of Metformin

The control and monitoring of the dosage of metformin are

contentious areas. From the analysis in this review, we suggest

that:

(i) as is generally recommended, metformin should be admin-

istered initially at a low rate in order to mitigate the adverse

gastrointestinal effects. The doses should be increased to a

maximum of 2.5–3 g daily in patients with good renal function

although lower dosage may be sufficient.

(ii) again, as is common, the response of patients should be

monitored by measurement of fasting levels of glucose and,

most importantly, HbA1c.

(iii) the dose of metformin should be individualized because

of intersubject variation in the bioavailability, (section 4) CLR

and CL/F (section 6) and response (section 7). Initially, the

maximum dose of metformin should be reduced proportionally

to the reduction in CLCR which can be estimated from the

plasma concentrations of creatinine, the bodyweight and the

age of the patient using, for example, the formulae of Cockcroft

and Gault.[102] For example, the initial target dosage in a

patient with a CLCR of 60mL/min (approximately 50% of

normal GFR) should be a maximum of 1.5 g although, again,

dosage should be commenced at a lower level. At 30mL/min,

a daily dose of 0.75 g daily should be the initial target dose.

These recommendations are made because CLR and CL/F of

metformin are approximately proportional to the CLCR, at

least down to about 20mL/min (figure 6). It is of note that the

product information on metformin recommends that lower than

normal doses should be used in patients with renal impairment

but the doses are not specified. There are insufficient data to

recommend routinely increasing the maximum dose with high

CLCR (>>120mL/min), although there is the pharmacokinetic

rationale to do so.

(iv) The plasma concentrations ofmetformin are notmonitored

in present clinical practice. However, we consider that this may

be useful, particularly in patients with CLCR below 60mL/min

in order to ensure that a safe dose is being administered. The

blood samples would be best taken at about 8 hours after

dosage with immediate-release tablets, or 4 or 16 hours after

dosage with the sustained-release tablets as the plasma

concentrations at these times approximate Cav,ss (figure 4)

Alternatively, the application of Bayesian methodology will

allow an estimate of Cav,ss which, we suggest, should not exceed

2.5mg/L. Monitoring the plasma concentrations should also

be valuable in patients who are failing to respond. Poor

compliance or actual poor adherence to treatment may then be

determined after careful discussion with the patients. Support

for monitoring the plasma concentrations comes from the

observation that the clinical response to metformin increases

with increasing dose and, further, that a higher dose ofmetformin

is required in patients with higher pretreatment fasting blood

glucose levels.[103] The monitoring of plasma concentrations of

metformin, however, requires clinical evaluation.

(v) The dosage of metformin must be suspended immediately if

any features of acute renal failure develop. This recom-

mendation follows from the high proportion of patients with

acute renal failure who developed lactic acidosis (section 6).

The dosage of metformin should be suspended in other states at

high risk of acute renal failure and lactic acidosis, such as acute

cardiac failure.

(vi) Any monitoring of plasma concentrations will require

concurrent examination of blood glucose through fasting levels

or by themeasurement of HbA1c. As discussed in section 5.1, low

levels of transporters, such as OCT1, may require higher than

normal dosage of metformin to produce an optimal response.

Acknowledgements

Financial assistance was obtained from NH&MRC Programme Grant

568612, Australian Research Council Grant LP 0990670 and St Vincent’s

Clinic Foundation Sister Mary Bernice Research Grant. Dr P. Timmins is



an employee of Bristol-Myers Squibb Company, who market immediate-

release and sustained-release tablets of metformin. All other authors have

no conflicts of interest to declare.

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E-mail: [email protected]

98 Graham et al.


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Clinical Pharmacokinetics 2011;courses.washington.edu/bioen316/Assignments/Sheen... · Clinical Pharmacokinetics of Metformin Garry G. Graham,1 Jeroen Punt,1 Manit Arora,1 Richard